Description: All three research projects in this Program depend very heavily on the use of a facility which can successfully and efficiently produce transgenic mice by conventional means and mutant animals by homologous recombination in embryonic stem cells. The director proposes to establish a gene manipulation Core built on an existing transgenic/ES cell facility at Caltech. The facility will be responsible for producing genetically engineered animals and will serve as a common central repository from which unmodified animals can be obtained. A centralized cell culture facility will be established to standardize the necessary set of techniques needed to produce animals with inactivated genes. This facility will serve as a producer of mutant cell lines (and animals) and also serve as a training resource for individuals who wish to learn and master this technology. To preserve transgenic mice and animals with targeted gene mutations, a cryopreservation facility is proposed.